Schedule-dependent antagonism of gemcitabine and cisplatin in human anaplastic thyroid cancer cell lines

Anaplastic thyroid carcinoma (ATC) affects primarily elderly patients, with a median survival of 4-12 months after diagnosis. presently, under clinica l investigation the combination of cisplatin (CDDP) and gemcitabine (GEM) h as promising activity in several of human tumor types, To develop new appro aches for therapy of ATC, we evaluated the antineoplastic activity of GEM a nd CDDP alone (1-h and 24-h drug exposure) or in combination in the ATC cel l lines SW1736, 8505C, C643, and HTh74. IC50 values were determined by the sulforhodamine B assay, activity was evaluated by the relative antitumor ac tivity (RAA) and drug interaction assessed by isobologram analysis. GEM see med to be active in ATC, with RAA ranging from 12-114 and CDDP only modestl y active (RAA, 0.24-1.4). In four different drug schedules tested, the drug combination was additive when GEM preceded CDDP exposure (combination inde x, similar to 1), whereas when CDDP preceded GEM exposure the combination w as significantly antagonistic (combination index, >1). In SW1736 and 8505C cells, we observed a strong S phase arrest and DNA synthesis inhibition 24 h after a 1-h exposure to an IC50 of CDDP. On the basis of molecular drug t argets, cell cycle arrest points, and DNA synthesis inhibition, a model was developed to explain the interaction observed for the combination of GEM a nd CDDP. In conclusion, GEM shows promising cytostatic activity in ATC, Interaction of GEM and CDDP was schedule and dose dependent, favoring a regime in which GEM is followed by CDDP, Additionally, our model system suggests that DNA- synthesis inhibition and S phase arrest may be important determinants for t he drug interaction between GEM and CDDP.